Scientists Reveal How Germs
Disrupt Cells' Distress Signals

Deadly mechanism, shared
by plant and animal pathogens, may yield target for new drugs.

UPTON, NY - Scientists studying the
germs that cause the Black Plague, plant infections, and colds
have discovered that these three very different microorganisms
share a common strategy: They all prevent the cells they're attacking
from calling out for help. In a paper appearing in the November
24 issue of Science, the scientists describe how all three organisms
produce a similar protein to interfere with the infected cells'
chemical signaling pathways, which are designed to alert the immune
system to attack the germs.

"Who would have predicted that
these three, diverse pathogens would use the same protein to disrupt
the same pathways to disable cell functions?" asks biologist
Walter Mangel of the U.S. Department of Energy's Brookhaven National
Laboratory, one of the collaborators. Understanding this common
mechanism may provide scientists with a new target for combatting
infections. The work may also provide insight into how cells communicate
in diseases such as cancer.

Mangel and Brookhaven biologist William
McGrath began investigating an enzyme from adenovirus, a cold
virus, in 1991. They showed that this enzyme was unique in its
genetic sequence and its three-dimensional structure (as determined
at Brookhaven's National Synchrotron Light Source). They postulated
that four crucial amino acids in the enzyme's active site gave
it its ability to cleave proteins, an essential step in infecting
cells.

Then, one day last year, Mangel received
an e-mail from Jack Dixon, a microbiologist at the University
of Michigan, who knew about Mangel's research and believed he
was working with a similar enzyme. This enzyme was produced by
Yersinia, the bacteria that cause the Black Death, or plague.

A model of the
structure of the protein-cutting enzyme produced by adenovirus,
a cold virus, which was determined at Brookhaven's NSLS. This
enzyme shares four crucial amino acids (in yellow) with enzymes
produced by microorganisms that cause the plague and some plant
infections.

Dixon had already shown that the Yersinia
enzyme, called YopJ, interrupted key signaling pathways in infected
cells, effectively disabling the host's immune response. But he
wasn't sure how it worked. If YopJ is similar to the adenovirus
enzyme, he reasoned, those four amino acids crucial to the adenovirus
enzyme should also be crucial to YopJ.

To test this hypothesis, Dixon mutated
each of the four amino acids. None of the four mutants of YopJ
was able to block the immune response. This showed that the four
critical amino acids are essential to YopJ's ability to disrupt
the cells' signaling pathways.

And, it turns out, adenovirus and Yersinia
are not alone. Homologous enzymes produced by plant pathogens
and plant symbionts (microbes that "infect" but live
in harmony with plant cells), have the same arrangement of the
four critical amino acids. This work was done by scientists at
Michigan and the University of California at Berkeley.

"All these data strongly suggest
that, like the adenovirus enzyme, YopJ and the enzymes of the
plant pathogens are acting as proteinases, enzymes that cleave
proteins, to disrupt universal cell signaling pathways,"
Mangel says.

The findings may be useful in medicine.
"Knowing how cells communicate with each other should allow
the development of means to prevent communication, for example
to prevent cancer cells from communicating with each other,"
adds Mangel. "And if cancer cells can't talk to one another,
they might not be able to grow into tumors."

Already, Mangel's laboratory has synthesized
drugs that inhibit adenovirus proteinase. "It will be interesting
to see what these drugs do with the Yersinia and the plant pathogens,"
he says.

The study was funded by the National
Institutes of Health, the U.S. Department of Energy, and the Walther
Cancer Institute. The State University of New York at Stony Brook
was an additional collaborator.

The U.S. Department of Energy's Brookhaven
National Laboratory creates and operates major facilities available
to university, industrial and government personnel for basic and
applied research in the physical, biomedical and environmental
sciences and in selected energy technologies. The Laboratory is
operated by Brookhaven Science Associates, a not-for-profit research
management company, under contract with the U.S. Department of
Energy.